This revised R01 grant application is focused on the study of T cell responses in HIV infected children. The course of HIV infection in children differs from adults, with many children experiencing higher and more persistent levels of HIV viremia. This could be related to the immaturity of the infant immune system or other immunological factors. In 3 specific aims, we undertake to understand more about the host pathogen interaction in HIV infected children, and how antiretroviral drugs affect these responses. In the first specific aim, we will determine the ability of young HIV uninfected children to mount T cell responses. We will study HIV infected children under 5 to determine the magnitude and breadth of HIV specific CD4+ and CD 8+ T cell responses. We show preliminary data that CD4+CD25+ T regulatory (Treg) cells can specifically suppress HIV specific responses and we will ascertain whether suppression of virus specific T cell responses might be due to higher Treg activity in these young children. There have been very few studies of differences in HIV immune responsiveness between racial groups. We present preliminary data that shows that Blacks have higher HIV specific T cell immune responses than Hispanics, when matched by age, viral load and CD4+ T cell count/percentage. In the second specific aim we will investigate how HLA and other genetic factors affect these results, if HIV specific immune responsiveness is related to the degree of racial admixing, and if other genetic, virologic or environmental factors could contribute to differential responses. Finally, as the HIV infected population in the USA matures into adolescence, we will perform an observational longitudinal study in the third specific aim to determine how levels of HIV specific immunity vary over time in relation to drug treatment, drug resistance and viral fitness. The goal of this grant application is to better understand immunopathogenic factors relevant to HIV infected children so they can be better placed to take advantage of developments in vaccines and new treatments.